A comparative immunohistochemical study of pancreatic islets inlaboratory animals (rats, dogs, minipigs, nonhuman primates)

Wieczorek, Grazyna; Pospischil, Andreas; Perentes, Elias

doi:10.1016/s0940-2993(98)80078-x

Cited by 92 publications

(113 citation statements)

References 107 publications

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“…The islets from the control and the liraglutide groups in the 52-week study had ;50% non-b-endocrine cells, with a substantial portion of those being a-cells (25-30% of endocrine cell mass), less d-cells (;15%), and only a few PP cells (4-7%). The fraction of the four endocrine cell types in our study is in agreement with data from human pancreata and a descriptive study in Cynomolgus monkeys (31)(32)(33)(34). The intraislet organization of the band non-b-cells was random, with no clear rodent-like mantle and core, but with a more complex subunit structure of mantles and cores, as characteristic for nonhuman primates and humans (23,35,36).…”

Section: Discussionsupporting

confidence: 88%

“…The control and liraglutide-dosed groups both showed a number of single glucagon-positive cells in the exocrine area, single cells and small clusters of glucagon-positive cells associated to the epithelial lining of both main and smaller ducts. This finding of small clusters and single endocrine cells is normal in Cynomolgus monkeys (34). A similar pattern with single cells in the exocrine areas and associated to ductal structures was observed for b-cells and less frequently with d-cells and PP cells, with no differences between groups.…”

Section: Discussionsupporting

confidence: 74%

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The Human GLP-1 Analogs Liraglutide and Semaglutide: Absence of Histopathological Effects on the Pancreas in Nonhuman Primates

et al. 2014

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Increased pancreas mass and glucagon-positive adenomas have been suggested to be a risk associated with sitagliptin or exenatide therapy in humans. Novo Nordisk has conducted extensive toxicology studies, including data on pancreas weight and histology, in Cynomolgus monkeys dosed with two different human glucagon-like peptide-1 (GLP-1) receptor agonists. In a 52-week study with liraglutide, a dose-related increase in absolute pancreas weight was observed in female monkeys only. Such dose-related increase was not found in studies of 4, 13, or 87 weeks’ duration. No treatment-related histopathological abnormalities were observed in any of the studies. Quantitative histology of the pancreas from the 52-week study showed an increase in the exocrine cell mass in liraglutide-dosed animals, with normal composition of endocrine and exocrine cellular compartments. Proliferation rate of the exocrine tissue was low and comparable between groups. Endocrine cell mass and proliferation rates were unaltered by liraglutide treatment. Semaglutide showed no increase in pancreas weight and no treatment-related histopathological findings in the pancreas after 13 or 52 weeks’ dosing. Overall, results in 138 nonhuman primates showed no histopathological changes in the pancreas associated with liraglutide or semaglutide, two structurally different GLP-1 receptor agonists.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 74%

The Human GLP-1 Analogs Liraglutide and Semaglutide: Absence of Histopathological Effects on the Pancreas in Nonhuman Primates

et al. 2014

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“…Our results confirmed previous studies on the composition of mouse islets but pointed to striking interspecies differences in the structure of islets of Langerhans, in particular between primate and rodent islets (see also ref. 4).…”

Section: Resultsmentioning

confidence: 99%

“…4), suggesting that a prototypical mammalian islet type may not exist. The wide species variability in islet cell composition and topography might reflect evolutionary adaptations to different dietary habits or other environmental constraints.…”

Section: Discussionmentioning

confidence: 99%

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The unique cytoarchitecture of human pancreatic islets has implications for islet cell function

Cabrera

Berman

Kenyon

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

1,107

967

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The cytoarchitecture of human islets has been examined, focusing on cellular associations that provide the anatomical framework for paracrine interactions. By using confocal microscopy and multiple immunofluorescence, we found that, contrary to descriptions of prototypical islets in textbooks and in the literature, human islets did not show anatomical subdivisions. Insulin-immunoreactive ␤ cells, glucagon-immunoreactive ␣ cells, and somatostatin-containing ␦ cells were found scattered throughout the human islet. Human ␤ cells were not clustered, and most (71%) showed associations with other endocrine cells, suggesting unique paracrine interactions in human islets. Human islets contained proportionally fewer ␤ cells and more ␣ cells than did mouse islets. In human islets, most ␤, ␣, and ␦ cells were aligned along blood vessels with no particular order or arrangement, indicating that islet microcirculation likely does not determine the order of paracrine interactions. We further investigated whether the unique human islet cytoarchitecture had functional implications. Applying imaging of cytoplasmic free Ca 2؉ concentration, [Ca 2؉ ]i, we found that ␤ cell oscillatory activity was not coordinated throughout the human islet as it was in mouse islets. Furthermore, human islets responded with an increase in [Ca 2؉ ]i when lowering the glucose concentration to 1 mM, which can be attributed to the large contribution of ␣ cells to the islet composition. We conclude that the unique cellular arrangement of human islets has functional implications for islet cell function.␣ cell ͉ ␤ cell ͉ cytoplasmic free Ca 2ϩ concentration ͉ insulin ͉ glucagon I n the last three decades, hundreds of individuals with type 1 diabetes mellitus have received allogeneic transplants of endocrine pancreas, the islets of Langerhans, to cure their chronic condition. In these patients, diabetes is reversed by transplanting cells capable of physiologically regulating insulin secretion. Determining the quality of islets obtained from cadaveric pancreata should be indispensable in this context. However, it is not known which physiological parameters correlate best with a fully functional islet capable of reversing diabetes after transplantation. There is a wealth of information about the physiology of rodent islets, but the biology of human islets remains poorly understood. As assays for determining islet quality are being developed by many laboratories in the field of islet transplantation, a reassessment of the structure and function of human islets is warranted.The islets of Langerhans are small organs located in the pancreas that are crucial for glucose homeostasis. Islets typically consist of four types of secretory endocrine cells, namely, the insulin-containing ␤ cells, the glucagon-containing ␣ cells, the somatostatin-containing ␦ cells, and the pancreatic polypeptideproducing (PP) cells. In rodent islets, the vastly predominating ␤ cells are clustered in the core of a generally round islet, surrounded by a mantle of ␣, ␦, and PP cells. Thus, ...

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Pathological Techniques in Toxicology

Greaves

2009

General, Applied and Systems Toxicology

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Histopathological evaluation remains an important part of the assessment of the adverse effects of xenobiotics on the whole organism. In addition to conventional special staining techniques and electron microscopy, new techniques involving immunocytochemistry, molecular biology and novel visualization procedures have provided additional objective techniques that have enabled better functional and morphological characterization of induced alterations in organs of the body. This chapter covers both conventional and new methods involved in the microscopical assessment of tissue changes induced by xenobiotics.

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A comparative immunohistochemical study of pancreatic islets inlaboratory animals (rats, dogs, minipigs, nonhuman primates)

Cited by 92 publications

References 107 publications

The Human GLP-1 Analogs Liraglutide and Semaglutide: Absence of Histopathological Effects on the Pancreas in Nonhuman Primates

The Human GLP-1 Analogs Liraglutide and Semaglutide: Absence of Histopathological Effects on the Pancreas in Nonhuman Primates

The unique cytoarchitecture of human pancreatic islets has implications for islet cell function

Pathological Techniques in Toxicology

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